5H{8 1{9 benzopyrano-{8 3,4-c{9 piperidines

ABSTRACT

A new series of 1,2,3,4-tetrahydro-5H-(1)benzopyrano(3,4c)pyridines and 5H-(1)benzopyrano-(3,4-c)piperidines, having C.N.S. and cardiovascular activity, and 5-oxo-1,2,3,4-tetrahydro5H-(1)benzopyrano(3,4-c)pyridines used as intermediates in the preparation thereof.

United States Patent [191 Pars et al.

[ Oct. 21, 1975 5H[1]BENZOPYRANO-[3,4-C]PIPERIDINES [75] Inventors:Harry G. Pars, Lexington; Felix E.

Granchelli, Arlington; Raj K. Razdan, Belmont, all of Mass.

[73] Assignee: Arthur D. Little, Inc., Cambridge,

Mass

[22] Filed: June 28, 1971 [21] Appl. No.: 157,658

Related US. Application Data [62] Division of Ser. No. 870,278, Oct. 30,1969, Pat. No. 3,635,993, which is a division of Ser. No. 642,223, May29, 1967, Pat. NO. 3,514,464.

[52] US. Cl. 260/293.55 [51] Int. Cl. C07D 491/04 [58] Field of Search260/29355, 295 T, 297 T [56] References Cited UNITED STATES PATENTS3,429,889 2/1969 Shulgin 260/295 3,514,464 5/1970 Pars et a1. 260/295Primary Examiner-Henry R. Jiles Assistant Examiner-G. Thomas ToddAttorney, Agent, or FirmBessie A. Lepper [57] ABSTRACT 1 Claim, N0Drawings 5H[ 1 ]BENZOPYRANO-[3,4-ClPlPERlDlNES This application is adivisional of our copending application Ser. No. 870,278, filed Oct. 30,1969, and now US. Pat. No. 3,635,993 which in turn was a divisional ofour application Ser. No. 642,223 filed May 29, 1967, now US. Pat. No.3,514,464. 7

This invention relates to novel chemical compositions of matter known inthe art of chemistry as l,2,3,4- tetrahydro-5H-[ l ]benzopyrano[3,4-c]pyridines and 5H-[ 1 ]benzopyrano[3,4-c]-piperidines having theformulas la, b and Ila, b, respectively:

IIb

and to 5-0xo-1,2,3,4-tetrahydro-5H- [1]benzopyrano[3,4-c]pyridines,useful as intermediates for the preparation of the compounds of formulasla, b and lla, b, and having the formulas llla, b:

IIIa

In the compounds of formulas la, b; lla, b; and llla, b above, R islower-alkyl; R is methyl or 3-methyl-2- octyl; R is a member of thegroup consisting of hydro gen, lower-alkyl, lower-alkanoyl,cycloalkyl-loweralkyl, cycloalkyl-lower-alkanoyl, lower'alkenyl,loweralkynyl, halo-lower-alkenyl (including fluoro-. chloro-, br0mo-,and iodo-lower-alkenyl), phenyl-lower-alkyl, phenyl-lower-alkanoyl,phenyl-lower-alkenyl, and phenyl-lower-alkynyl; and R is hydrogen,lower-alkyl. lower-alkanoyl, carbamyl, N-lower-alkylcarbamyl,N,N-di-lower-alkylcarbamyl, or phosphonyl, R being methyl only when R ishydrogen, loweralkanoyl, cycloalkyl-lower-alkyl,cycloalkyl-lower-alkanoyl, lower-alkenyl, lower-alkynyl,halo-lower-alkenyl, phenyllower-alkyl, phenyl-lower-alkanoyl,phenyl-loweralkenyl, or phenyl-lower-alkynyl.

As used herein, the term lower-alkyl" means saturated, monovalentaliphatic radicals, including straight or branched-chain radicals offrom one to six carbon atoms, as illustrated by, but not limited tomethyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, amyl, hexyl, andthe like.

As used herein, the term lower-alkenyl means mono-valent, aliphaticradicals of from 3 to 7 carbon atoms which contain at least one doublebond, and are either straight or branched-chain, as illustrated by, butnot limited to l-(2-propenyl), l-(3-methyl-2- propenyl), l-(l,3-dimethyl-2-propenyl), l-(2- hexenyl), and the like.

As used herein, the term lower-alkynyl means mono-valent, aliphaticradicals, of from 3 to 7 carbon atoms which contain at least one triplebond, and are either straight or branched-chain, as illustrated by, butnot limited to l-(2-propynyl), l( l-methyl-Z- propynyl), 1-(2-heptynyl),and the like.

As used herein, the term cycloalkyl" means cyclic, saturated aliphaticradicals of from 3 to 8 carbon atoms, as illustrated by, but not limitedto cyclopropyl, cyclobutyl, Z-methylcyclobutyl, cyclohexyl, 4-methylcyclohexyl, cyclooctyl, and the like.

As 'used herein. the term lower-alkanoyl means saturated, monovalent,aliphatic radicals derived from a mono-carboxylic acid, includingstraight or branched-chain radicals of from 1 to 6 carbon atoms, asillustrated by, but not limited to formyl, acetyl, pro pionyl,a-methylpropionyl, butyryl, hexanoyl, and the like.

As used herein, the terms phenyl-lower-alkyl", phenyl-lower-alkanoyl,phenyl-lower-alkenyl", and phenyl-lower-alkynyl" mean a monovalentradical consisting ofa phenyl nucleus bonded to the rest of the moleculethrough. respectively, a divalent loweralkylene radical of from 1 to 4carbon atoms as illustrated by, but not limited to methylene,l,lethylene,l,2-ethylene, 1,3-propylene, l,2-propylene, 1,4-butylene,and the like, or through a divalent loweralkenylene radical of from 2 to4 carbon atoms, as illus trated by, but not limited to l,2-ethenylene,l,3-(lpropenylene), l,3-(l-butenylene), 1,4-(2-butenylene), and thelike, or through a divalent lower-alkynylene radical of from 2 to 4carbon atoms, as illustrated by, but not limited to 1,2-ethynylene,1.3-propynylene, 1,3-(1-butynylene), and the like. Here and elsewherethroughout this specification, it will be understood the benzene ring ofphenyl can bear any number and kind of substituents such as would occurto the man skilled in organic chemistry. Solely for illustration. andwithout limitation, such substituents include lower-alkyl, lower-alkoxy,halo (chloro, bromo, iodo, or fluoro), nitro, lower-alkylmercapto. andthe like.

The compounds of formulas la, b where R is hydrogen are prepared byreacting an 8-alkyl-l0-hydroxy-5- oxo-l ,2,3,4-tetrahydro-5H-[ l]benzopyrano[3,4- c]pyridine or a l0-alkyl-8-hydroxy-5-oxo-l ,2,3,4-tetrahydro-5H-[ l ]benzopyrano[3,4-cl-pyridine, having the respectiveformulas llla and lllb, with a loweralkyl magnesium halide asillustrated by the equation:

Ia,b

where R R and R have the meanings given hereinabove, and Hal representshalogen. The reaction is carried out in an organic solvent inert underthe conditions of the reaction. Suitable solvents are diethyl ether,dibutyl ether, tetrahydrofuran, anisole, pyridine, and the like. It ispreferred to add a solution of the 8-alkyl-l0- hydroxy-S-oxo- 1,2,3,4-tetrahydro-5H- [l ]benzopyrano[3,4-c]pyridine orlO-alkyl-8'hydroxy- 5-oxo-l ,2,3,4-tetrahydro-5H-[ 1 ]benzopyrano[3,4-c]pyridine in a pyridine or anisole solution, or in a mixture of thesesolvents, to a solution of the Grignard reagent in anisole.

The compounds of formulas Illa, b in turn are prepared by reacting a l-R-3carbo-lower-alkoxy-4- piperidone of formula IV with a5-alkylresorcinol of formula V. The reaction is carried out in a mixtureof concentrated sulfuric acid and phosphorus oxychloride or in thepresence of other acidic condensation agents such as aluminum chloride,hydrogen chloride, or polyphosphoric acid and is illustrated by theequation:

IIIa

HO 2 COOAlk l-(b) IIIb where R and R are defined as above, and Alk isloweralkyl. Y

As indicated by the reaction scheme above, the ring closure of the 1-R-3-carbo-lower-alkoxy4-piperidone with the S-alkylresorcinol can takeplace either by cyclization at the 2-position of'the 5-alkylres0rcinol,as

indicated by the arrow (a), to produce the 8-alkyl-l0- hydroxy 5-ox0-l,2,3,4-tetrahydro-5H- [l]benzopyrano[3,4-clpyridines of formula llla orby cyclization at the 4-position of the S-alkylresorcinol, as indicatedby the arrow ([2), to produce the lOalkyl-8- hydroxy-S-oxo-l,2,3,4-tetrahydro-5H- [1]benzopyrano[3,4-c]pyridinesof formula lllb.Generally either the compounds of formula Illa or of formula lllb areproduced by either S-methylresorcinol (R is CH3) Or by5-(3-methyl-2-octyl)resorcinol (R is CHCH CHCH C 1 ut in the lattercase, the predominant products are the compounds of formula llla owingto the partial steric hindrance of the 4-position of the resorcinol bythe rather bulky 3-methyl-2-octyl group in the adjacent 5-position whichinhibits cyclization at the 4-position.

The intermediate S-methyland 5 -(3-methyl-2- octyl)-resorcinols offormula V are known in the art.

The intermediate l-R;,-3-carbo-lower-alkoxy-4- piperidones of formula IVare prepared by the method of Prill and McElvain, J. Am. Chem. Soc. 55,1233(1933) and of McElvain and Vozza, J. Am. Chem. Soc. 71, 896(1948).

The compounds of formulas ,la and lb where R is hydrogen are alsoadvantageously prepared by catalytically debenzylating, with hydrogen inthe presence of a catalyst, the compounds of formulas la. b hereinabovewhere R, is benzyl. The reaction is preferably carried out in an organicsolvent inert under the conditions of the reaction, for examplemethanol, ethanol, isopropanol, and the like. Suitable catalysts areplatinum or palladium-on-charcoal. A preferred catalyst ispalladium-on-charcoal. v

The compounds of formulas la, b or lla, b, where R, iscycloalkyl-lower-alkyl, lower-alkenyl, loweralkynyl, halo-lower-alkenyl,phenyl-lower-alkyl, phenyl-loweralkenyl, or phenyl lower alkynyl areprepared by reacting the corresponding compounds of formulas la, b orlla, b, where R, is hydrogen with a cycloalkyl-loweralkyl,lower-alkenyl, lower-alkynyl, halo-lower-alkenyl, phenyl-lower-alkyl,phenyl-loweralkenyl, or phenyllower-alkynyl halide, respectively. Thereaction is preferably carried out in an organic solvent inert under theconditions of the reaction. for example methanol, ethanol, isopropanol,or dimethylformamide, and in the presence of an acid-acceptor. Thepurpose of the acidacceptor is to take up the hydrogen halide split outduring the course of the reaction and is a basic substance which formswater-soluble salts readily separable from the reaction mixture.Suitable acid-acceptors are alkali metal carbonates or bicarbonates, forexample sodium or potassium carbonate, or bicarbonate, or alkali metalhydroxides, for example sodium or potassium hydroxide. The reaction canalso be carried out in the presence of a molar excess of the bases offormulas la, b or Ila, b where R is hydrogen. A preferred acid-acceptoris sodium carbonate, and a preferred solvent is ethanolv The compoundsof formulas la, b or lla, b where R,

is lower-alkanoyl, cycloalkyl-lower-alkanoyl. or phenyl-lower-alkanoylare prepared by reacting the corresponding compounds of formulas la. bor lla, b where R, is hydrogen with an acid halide or anhydride of alower-alkanoic, cycloalkyl-lower-alkanoic, or phenyl-lower-alkanoicacid, respectively. The reaction is preferably carried out in an organicsolvent inert under the conditions of the reaction, for example benzene.toluene, xylene, and the like, and in the presence of a basic catalyst,for example pyridine, triethylamine, dimethylaniline, and the like. Apreferred solvent is benzene, and a preferred basic catalyst ispyridine.

The compounds of formulas la, b or Ha, I; where R;, iscycloalkyl-lower-alkyl and phenyl-loweralkyl can also be prepared byreducing, with an alkali metal aluminum hydride, the compoundsofformulas la, b or lla, b where R is cycloalkyl-lower-alkanoyl orphenylloweralkanoyl, respectively, and where R is hydrogen orlower-alkyl. The reaction is preferably carried out in an organicsolvent inert under the conditions of the reaction, for example diethylether, tetrahydrofuran, dibutyl ether, and the like.

The S-alkyl-lO-hydroxy-S,5-di-lower-alkyl-5H-[ lbenzopyrano[3,4-c]piperidines and 10-alkyl-8-hydroxy-S,S-di-lower-alkyl-SH-[ l ]benzopyrano[ 3,4- clpiperidines offormulas Ila and llb, respectively, are prepared by reducing withhydrogen over a suitable catalyst the8-alkyl-lO-hydroxy-S,5-di-lower-alkyll,2,3,4tetrahydro5H-[ l]benzopyrano[3,4-c]- pyridines andlO-alkyl-S-hydroxy-S,5-di-lower-alkyll,2,3,4-tetrahydro-5H-[ l]benzopyrano[ 3,4- clpyridines of formulas la and lb, respectively,where R R and R have the, meanings given above and R is hydrogen,loweralkyl, lower-alkanoyl, cycloalkylloweralkyl,cycloalkyl-loweralkanoyl, phenyl-loweralkanoyl, or phenyl-lower-alkyl.The reaction is carried out in an organic solvent inert under theconditions of the reaction, for example methanol, ethanol, isopropano],and the like. Suitable catalysts include palladiumon-charcoal, platinum,Raney nickel, and the like. A preferred catalyst is Raney nickel.

The ester and ether derivatives of the compounds of formulas la, b andIla, b, that is the compounds where R, is lower-alkyl, lower-alkanoyl,carbamyl, N-loweralkylcarbamyl, N,N-di-lower-alkylcarbamyl, orphosphonyl are prepared by reacting the corresponding compounds whereR., is hydrogen, preferably in the presence of a basic catalyst, with alower-alkyl halide, to produce the compounds where R is lower-alkyl;with a lower-alkanoic anhydride (or mixed anhydride), to produce thecompounds where R, is lower-alkanoyl; with a molar equivalent ofphosgene followed by reaction of the resulting chloroformate withammonia, a lower-alkylamine, or a di-lower-alkylamine, to produce thecompounds where R, is, respectively, carbamyl,

N-lower-alkylcarbamyl, or N,N-di-loweralkylcarbamyl; or with onemolarequivalent amount of phosphorus oxychloride followed by reaction ofthe resulting dichlorophosphinate with aqueous sodium or potassiumcarbonate, to produce the compounds where R, is phosphonyl. Suitablesolvents are benzene, toluene, xylene, and the like, and suitable basiccatalysts are alkali metal carbonates, bicarbonates, or hydroxides,dimethylaniline, pyridine, and the like.

The acid-addition salts of the bases herein described are the form inwhich the bases are most conveniently prepared for use and are the fullequivalents of the subject matter specifically claimed. The acidmoieties or anions in these salt forms are in themselves neither novelnor critical and therefore can be any acid anion or acid-like substancecapable of salt formation with the free base form of the compounds. Thepreferred type of salts are water-soluble pharmacologicallyacceptablesalts, that is, salts whose anions are relatively innocuous to theanimal organisms in pharmacological doses of the salts, so that thebeneficial physiological properties inherent in the free base are notvitiated by side effects ascribable to the anions; in other words, thelatter do not substantially affect the pharmacological propertiesinherent in the cations. 1n practicing the invention, it has been foundconvenient to form the hydrochloride salt. However, other appropriatepharmacologically-acceptable salts within the scope of the invention arethose derived from mineral acids such as hydrobromic acid, hydriodicacid, nitric acid, phosphoric acid, sulfamic acid, and sulfuric acid;and organic acids such as acetic acid, citric acid, tartaric acid,lactic acid, methanesulfonic acid, ethanesulfonic acid, quinic acid, andthe like, giving the hydrobromide, hydriodide, nitrate, phosphate,sulfamate, sulfate, acetate, citrate, tartrate, lactate,methanesulfonate, ethanesulfonate, and quinate, respectively.

Although pharmacologically-acceptable salts are preferred, those havingtoxic anions are also useful. All acid-addition salts are usefulintermediates as sources )f the free base form even if the particularsalt per se s not desired as the final product, as for example when :hesalt is formed only for purposes of purification or dentification, orwhen it is used as an intermediate in Jreparing apharmacologically-acceptable salt by ion- :xchange procedures.

The compounds of formulas 1a, b and 11a, b have been ihOWfl to possessC.N.S. and cardiovascular activity as :videnced by gross overt changesinduced by intraveious administration in mice in standard testsinvolving )bservations of psychomotor activity, reactivity to .timuli,and ability to perform normal, non-conditioned notor tasks. Thisactivity indicates their usefulness as sychotropic agents.

The compounds can be prepared for use by disolving under sterileconditions a salt form of the comiounds in water (or an equivalentamount of a nonoxic acid if the free base is used), or in aphysiologcally compatible aqueous medium such saline, and tored inampoules for intramuscular injection. Alterlatively, they can beincorporated in unit dosage form .s tablets or capsules for oraladministration either lone or in combination with suitable adjuvantssuch as alcium carbonate. starch, lactose, talc, magnesium tearate, gumacacia, and the like. Still further, the ompounds can be formulated fororal administration 1 aqueous alcohol, glycol, or oil solutions oroil-water mulsions in the same manner as conventional medicialsubstances are prepared.

The molecular structures of the compounds of our ivention were assignedon the basis of study of their ifrared, ultraviolet, and NMR spectra andtheir trans- )rmation products, and confirmed by the corresponencebetween calculated and found values for the eleientary analyses forrepresentative examples.

25 tained 7.3 g. of

The following examples will further illustrate the invention without,however, limiting it thereto.

EXAMPLE 1 -Hydroxy-8-( 3methyl-2-octyl )-3 ,5 ,S-trimethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-cjpyridine A. 10-Hydroxy-5-oxo-3-methyl-8-( 3-methyl-2-octyl 0l,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridine1-Methyl-3-carbethoxy-4 piperidone hydrochloride, (42 g., 0.19 mole) wasadded in portions to 27.8 g. (0.12 mole) of5-(3-methyl-2-octyl)resorcinol with stirring, and 48 ml. of concentratedsulfuric acid was then added dropwise to the mixture at roomtemperature. The mixture was then treated with 21 ml. of phosphorusoxychloride, stirred at room temperature for 78 hours, neutralized withaqueous potassium bicarbonate, and the product extracted intochloroform. The organic extracts were washed first with bicarbonatesolution and then with water, dried over anhydrous sodium sulfate,'andtaken to dryness. The crude product (44 g.) was extracted with five 350ml. portions of boiling acetonitrile, and from the fifth extract therewas ob- 10-hydr0xy-5-oxo-3-methyl-8-(3- methyl-2-octyl)-l,2,3,4-tetrahydro-5H-[ 1 ]benzopyrano[3,4-c]-pyridine, m.p. 169--173C.

B. 10-Hydroxy-8-( 3-methyl-2-octyl )-3 ,5 ,S-trimethyl-1,2,3,4-tetrahydro5H-[1]benzopyrano[ 3,4-clpyridine A solution of 3.5 g.(0.01 mole) of 10-hydroxy-5- oxo-3-methyl-8-(3-methyl-2-octyl)-1,2,3,4-tetrahydro- 5H-[1]benzopyrano[3,4-clpyridine, dissolved in 65 ml.

of pyridine, was added dropwise to a solution of 0.1 mole of methylmagnesium iodide in 100 ml. of anisole. When addition was complete, themixture was stirred at 30-45C. for about 8 hours, cooled, and the excessGrignard reagent decomposed with 100 ml. of water.

The mixture was then acidified with 300 ml. of 4N sulfuric acid, andsteam distilled to remove the anisole. The aqueous residue was thenbasified by the addition of solid sodium carbonate, and the pyridineremoved 45 by steam distillation. The solid which separated from thecooled reaction mixture was collected and dried giving 3.36 g. of theproduct in free base form. The latter was converted to the hydrochloridesalt in ethyl acetate and recrystallized from acetonitrile giving 1.4 g.of

10-hydroxy-8-(3-methyl-2-octyl)-3,5,5-trimethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridine hydrochloride, m.p.281283C.

Anal. Calcd. for C H NO .HCl: C, 70.65; H, 9.39; N, 3.43

Found: c, 71.07; H, 9.45; N, 3.42.

EXAMPLE 2 5 ,S-Dimethyl- 1 O-hydroxy-8-( 3-methy1-2-octy11,2,3,4-tetrahydro-5H-[1]-benzopyrano[3,4-

6Q c]pyridine stirring, and the mixture was then treated dropwise withcooling with 22 ml. of concentrated sulfuric acid. When addition wascomplete, 6 ml. of phosphorus oxychloride was added all at once, and themixture stirred for 16 hours at room temperature. Isolation of theproduct in the form of its hydrochloride salt and recrystallization fromacetonitrile gave 6.5 g. of 3-benzyl-l0-hydroxy-8-(3-methyl-2-octyl)-5-oxo-1,2,3 ,4- tetrahydro-5H-[ l]benzopyrano[3,4-c]pyridine hydrochloride, m.p. 236240C.

Anal. Calcd. for C H NO .HCI: C 71.55; H, 7.50; N, 2.97

Found: C, 71.29; H, 7.74; N, 2.96.

B. 3-Benzyl-5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-1,2,3,4-tetrahydro5H-[1 ]benzopyrano[ 3,4- c]pyridinehydrochloride was prepared from 11.5 g. (0.026 mole) of 3-benzyl-10-hydroxy-8-( 3-methyl-2-octyl )-5-oxo-l ,2,3,4- tetrahydro-5H-[ 1]benzopyrano-[3,4-c]pyridine hydro chloride and 0.24 mole of methylmagnesium iodide in anisole using the procedure described above inExample l-B. The crude product, isolated in the form of thehydrochloride salt, was recrystallized from ethyl acetate giving 2.9 g.of 3-benzyl-5,5-dimethyllO-hydroxy-8(3-methyl-2-octyl)-l,2,3,4-tetrahydro-5H- [1]benzopyrano[3,4-c]pyridine hydrochloride, 149-152C.

Anal. Calcd. for C H NO .HCl: C, 74.43; H, 8.74; N, 2.89

Found: C, 73.56; H, 8.89; N, 2.83.

C. 5 ,S-Dimethyll O-hydroxy-8-( 3methyl-2-octyl l,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c1pyridine A solution of 10 g. (0.024 mole) of3-benzyl-5,5- dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-l ,2,3,4-tetrahydro-5H-[ l ]benzopyrano[ 3,4-c]pyridine, dissolved in 150 ml. ofabsolute ethanol and 30 ml. of gla cial acetic acid, was reduced withhydrogen at 45.5 pounds p.s.i. over 0.7 g. of a 10% palladium-oncharcoalcatalyst. When reduction was complete, the solution was filtered fromthe catalyst, the filtrate evaporated to dryness, and the residue takeninto chloroform and washed with aqueous potassium bicarbonate. Theorganic layer was then washed with water, dried over sodium sulfate,evaporated to dryness, and the red solid residue recrystallized oncefrom acetonitrile and once from benzene to give 2.6 g. of5,5-dimethyl-lhydroxy-8-(3-methyl-2-octyl)-1,234-tetrahydro-5H-[1]benzopyrano[3,4-c pyridine, m.p. l68-170C.

Anal. Calcd. for C H NO C, 77.26; H, 9.87; N,

Found: C, 77.32; H, 10.06; N, 4.14.

D. .S-Dimethyll 0-hydroxy-8-( 3-methyl2-octyl )3( 2-propynyl)-l,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4- clpyridinehydrochloride A mixute of 1.6 g. (0.004 mole) of 5,5-dimethyl--hydroxy-8-(3-methyl-2-octyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridine,' 0.52 g. (0.004 mole) of3-bromo-1-propyne, 0.6 g. (0.006 mole) of anhy drous sodium carbonate,0.1 g. of sodium iodide, and 30 ml. of absolute ethanol was stirred andrefluxed under nitrogen for 16 hours, cooled, filtered, and the filtrateevaporated to dryness. The red gummy residue was extracted wtihpetroleum either (b.p. 3060C.), the extracts concentrated to a smallvolume, filtered to remove about 300 mg. of a pink solid, and thefiltrate evaporated to dryness. The resulting was taken into ether, thesolution saturated with anhydrous hydrogen chloride, diluted withpetroleum ether, and cooled to give 372 mg. of5,5-dimethyl-l0-hydroxy-8-(3-methyl- 2-octyl )-3-( 2-propynl l ,2,3,4-tetrahydro-5 H- [1]benzopyrano[3,4-c]pyridine hydrochloride, l20125C.

Anal. Calcd. for C H NO HCI: C, 72.28; H. 8.86; N, 3.24

Found: C, 71.91; H, 8.43; N, 3.19.

EXAMPLE 3 3-Allyl-5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl 1 ,2,3,4-tetrahydro-5H-[1]benz0pyrano-[3 ,4- c]pyridine hydrochloride.

A mixture of 1.6 g. (0.004 mole) of 5.5-dimethyl- 10-hydroxy-8-(3-methyl-2-octyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridine, 0.51 g. (0.004 mole) of3-bromo-l-propene, 0.6 g. (0.006 mole) of anhydrous sodium carbonate,and 30 ml. of absolute ethanol was stirred and refluxed under nitrogenfor 16 hours, cooled, filtered, and the filtrate evaporated to dryness.The residue was taken into petroleum ether (b.p. 3060C.), filtered, andthe filtrate saturated with anhydrous hydrogen chloride to give a yellowgummy precipitate which was recrystallized from a petroleum ether-ethylacetate mixture giving 054 g. of 3-a11yl-5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-l ,2,3,4-tetrahydro-5H-[l]benzopyrano [3,4-c]-pyridine hydrochloride, m.p.2082l0C.

Anal. Calcd. for C H NO .HCl: C, 71.94; H, 9.29 N, 3.22

Found: C, 72.08; H, 9.31; N, 3.04.

EXAMPLE 4 3( trans-3-Chloroallyl )-5 ,S-dimethyll O-hydroxy-8-( 3-methyl-2-octyl)-1 ,2,3,4-tetrahydro-5H- [l]benzopyranol3,4-c1pyridinehydrochloride was prepared from 1.6 g. (0.004 mole) of5,5-dimethyll0-hydroxy-8-(3-methyl-2-octyl)-1,2,3 ,4-tetrahydro- 5H-[ 1]benzopyrano[3,4-c]pyridine, 0.48 g. (0.004 mole) oftrans-1,3-dichloro-1-propene, 0.6 g. (0.006 mole) of anhydrous sodiumcarbonate, and 30 ml. of absolute ethanol using the manipulativeprocedure above in Example 3. The crude product was isolated in the formof its hydrochloride salt, and the latter recrystallized once from apetroleum ether/ethyl acetate mixture, and once from an ethylacetate/ethanol mixture giving 0.31 g. of3-(trans-3-chloroallyl)-5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-1,2,3,4-tetrahydro-5H'[1]benzopyrano[3,4-c]pyridine hydrochloride, m.p. 250253C.

Anal. Calcd. for C H ClNO .HCl: C. 66.66; H, 8.39; N, 2.99

Found: c, 6641; H, 8.52; N, 2.88.

EXAMPLE 5 l0Hydroxy-3-( 2-propynyl )-5 ,5 ,8-trimethyl-l ,2,3 ,4-tetrahydro-5H-[ 1 ]benzopyrano[3 ,4-c] pyridine 3-Benzyl lO-hydroxy-8-methyl-5-oxo- 1 1 l.2,3,4tetrahydro-Hl l]benzopyranol3,4-clpyridine l-Benzyl-3-carbethoxy-4-piperidonehydrochloride. (104 g. 0.33 mole) was mixed with 50 g. (0.4 mole) ofS-methylresorcinol, and the mixture treated dropwise over a period of 1hour with 160 ml. of concentrated sulfuric acid. Phosphorus oxychloride(60 ml.) was then added all at once, and the mixture stirred at roomtemperature for 16 hours. Isolation of the product according to theprocedure described above in Example l-A afforded 0.6 g. of3-benzyl-l0-hydroxy-8-methyl- 5-oxo-1,2,3,4-tetrahydro-5H-[ l]benzopyrano[3,4-c]- pyridine, m.p. 222224C.

Anal. Calcd. for C H NO C, 74.74; H, 5.96; N, 4.36

Found: C, 74.58; H, 5.86; N, 4.29.

B. -Hydroxy-8-methyl-5oxo-1,2,3,4-tetrahydro-5H-[1]benopyrano[3,4-c]pyridine was prepared by catalytic debenzylation of2 g. (0.006 mole) of 3-benzyl-10-hydroxy-8-methyl-5-oxo-1,2,3,4-tetrahydro5H-[1]benzopyrano[3.4-c]pyridine in 100 ml. of glacial aceticacid and 50 m1. of absolute ethanol under 54 pounds p.s.i. of hydrogenover 0.5 g. of 10% palladium-on-charcoal using the manipulativeprocedure described above in Example 2-C. Recrystallization of the curdeproduct from ethanol afforded 0.1

g. of l0-hydroxy-8-methyl-5-oxo1,2,3,4-tetrahydro- 5H-[ 1]benzopyrano[3,4-c]pyridine, m.p. 250-253C. Anal. Calcd. for C H NO C,67.52; H, 5.67; N. 606

Found: C, 67.24; H, 5.71; N, 6.04.

C. l0-Hydroxy-8-methyl-5 -oxo-3-( 2propynl )-1 ,2,3 ,4- tetrahydro-5H-[1]benzopyrano[ 3.4-]pyridine D.l0Hydroxy-3-(2-propynyl)-5,5,8-trimethyl-l,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-clpyridine is prepared by reactinglO-hydroxy-8-methyl-5-oxo-3- (2-propynyl l ,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-cjpyridine with methyl magnesium iodide in anisoleaccording to the manipulative procedure described above in Example l-B.

EXAMPLE 6 3-Benzyl-10-hydroxy-5,5,8-trimethyl-1,2,3,4- tetrahydro-5H-[l]-benzopyrano[3,4-c1pyridine was prepared form 15.6 g. (0.048 mole) of3-ben2yll0-hydroxy-8-methyl-5-oxo-l,2,3,4-tetrahydro-5H- [1]benzopyrano[3,4-c]pyridine and 0.5 mole of methyl magnesium bromide in350 m1. of anisole, and 120 ml.

of pyridine using the manipulative procedure described above in Example1-B. The crude product was recrystallized from acetonitrile to give 4.0g. of 3-benzyl-10- hydroxy-5 5,S-trimethyl-1,2,3.4-tetrahydro-5H-[1]benzopyranol3,4c]pyridine. m.p. 206208C.

Anal. Calcd. for C H NO C, 78.77; H. 7.51; N, 4.18

Found: C. 79.15; H. 7.36; N. 4.28.

EXAMPLE 7 5.5-Dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-3-(2- propynyl)-1 ,2,3,4-tetrahydro-5H-[ l ]benzopyrano[3,4

-c]-pyridine hydrochloride A. 10 -Hydroxy-8-(3-methyl-2-octy)-5-oxol,2,3 ,4

-tetrahydro-5 H-[1]benzopyrano[3,4-c]pyridine was prepared by catalyticdebenzylation of 3-benzyl- 10-hydroxy-8-( 3-methyl-2-octyl)-5-oxo-1,2,3,4- tetrahydro-5H-[l]benzopyrano[3.4-c1pyridine in 200 ml. ofabsolute ethanol and 20 ml. of glacial acetic acid under 50 poundsp.s.i. of hydrogen over 1 g. of a 1071 palladium-on-charcoal catalystusing the manipulative procedure described above in Example 2-C. Thecrude product was recrystallized twice from acetonitrile giving 1.9 g.of 10-hydroxy-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano-[3,4- c]pyridine, m.p. 177-179C.

Anal. Calcd. for C H NO C, 73.43; H, 8.51; N, 4.08

Found: C, 73.06; H, 8.47; N, 4.23.

l0-Hydroxy-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4- tetrahydro-5H-[1]benzopyranol3,4-c]pyridine was also prepared by reaction of 5.8 g.(0.025 mole) of 3-carbethoxy-4-piperidone hydrochloride with 5.9 g.(0.025 mole) of 5-(3-methyl-2-octyl)-resorcinol in 11.5 ml. ofconcentrated sulfuric acid and 4.5 m1. of

phosphorus oxychloride using the manipulative procedure described abovein Example 1-A. Recrystallization of the crude product from acetonitrileafforded 0.75 g. of10-hydroxy-8-(3-methyl-2-octyl)-5-oxol,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-clpyridine, m.p. l79l8lC.

10-Hydroxy-8-( 3'methyl'2-octyl )-5-oxo-3-( 2-propynyl)-l,2,3,4-tetrahydro-5H-I 1]benzopyrano[3 ,4- c]pyridinehydrochloride Found: C, 68.86; H, 7.79; N, 3.37.

5 ,S-Dim cthyll O-hydroxy-8-( 3-methyl-2-octyl )-3-( 2propynyl)-1,2,3-,4-tetrahydro-5H-'[ 1]benzopyrano[3,4-

c]pyrdine hydrochloride can be prepared by reaction of l -hydroxy-8 -(3-methyl-Z-octyl)--oxo-3-(2-propynyl)-l,2,3,4- tetrahydro-5H-[ l]benzopyrano[ 3,4-c]-pyridine hydrochloride with methyl magnesium iodidein anisole, using the manipulative procedure described above in Examplel-B.

EXAMPLE 8 5,5-Di-(1-hexyl)-l0-hydroxy-3-methyl-8 t3-methyl2- Ioctyl)-1,2,3,4-tetrahydro-5H-[l]benzopyrano[ c]pyridine Following aprocedure similar to that described in Example l-B hereinabove,-hydroxy-3-methyl-8-(3- methyl-2-octyl)-l,2,3,4-tetrahydro-5l-l- [l]benzopyrano[3,4-c]pyridine is reacted with n-hexyl magnesium bromide inanisole to give S,5-di-( l-hexyl l0-hydroxy-3-methyl- 8-(3-methyl-2-octyl )-l ,2,3,4- tetrahydro-5H-[ l ]benzopyrano[3,4-c]pyridine.

EXAMPLE 9 3-Cinnamyl-5,S-dimethyl-lO-hydroxy-8( 3-methyl-2-octyl)-l,2,3,4-tetrahydro-5H[1]benzopyrano[3;4-

c]pyridine Following a procedure similar to that described in' EXAMPLE1i 5,5-Dimethyl-10-hydroxy-8(3-methyl-2-octyl)-3- phenylacetyl-l,2,3,4-tetrahydro-5H- [l ]benzopyrano[3,4-c]pyridine By reactionof5.5-dimethyl-10-hydroxy-8-(3-methyl 2octyl)- l ,2,3,4-tetrahydro-5H-[l ]benzopyrano[3,4- clpyridine with phenylacetyl chloridein the presenceof pyridine in a benzene solution, there can be obtained5,5-dimethyl-10-hydroxy-8-(3-methyl 2-octyl)-3-phenylacetyl-l,2,3,4-tetrahydro-5H- [l]benzopyranol3,4-c]pyridine.

EXAMPLE 12 5,5Dimethyl-l 0-hydroxy-8-(3-methyl-2-octyl)-3-(2-phenylethyl )-l ,2,3,4-tetrahydro-5H- [l]benzopyrano[3,4-c]pyridine byreduction of 5,5-dimethyl-l0-hydroxy-8-(3-methyl-Z-octyl)-3phenylacetyl-l ,2,3,4-tetrahydro-5 H-[1]benzopyrano[3,4-c1pyridine with lithium aluminum hydride intetrahydrofuran solution, there can be obtained5,5-dimethyl-lO-hydroxy-8-(3-methyl-2-octyl)- 3-(2-phenylethyl )-l,2.3.4-tetrahydro-5H- [l]benzopyrano[3,4c]pyridine.

EXAMPLE 13 5 5-Dimethyl- 1 0-hydroxy-8-( 3-methyl-2-octyl )-3-[ 2 imethylphenyl)ethyl]-1,2,3 ,4-tetrahydro-5 H-[l]benzopyrano[3.4-c]pyridine Following a procedure similar to thatdescribed in Example 3 hereinabove, 5.5-dimethyl-10-hydroxy-8-(3-methyl2-octyl )-l ,2,3,4-tetrahydro-5H- [l]benzopyrano[3,4-c]pyridineis reacted with 2-(4- methylphenyl)ethyl bromide in absolute ethanol inthe presence of anhydrous sodium carbonate to give 5.5-dimethyl-l0-hydroxy-8-(3-methyl-2-octyl)-3-[2-(4- methylphenyl )ethyl]-l ,2,3,4-tetrahydro-5H- [l]benzopyrano[3,4-c]pyridine.

EXAMPLE l4 5,5-Dimethyl-lO-hydroxy-8-(3-methyl-2-octyl)-3-[3- (3,4dim'ethoxyphenyl)-propyl]-1,2,3,4-tetrahydro- 5H-[ 1]-benz0pyrano[3,4-c]pyridine I Following a procedure similar to thatdescribed in Example 3 hereinabove, 5,5-dimethyl-l0-hydroxy-8-(3-methyl-2-octyl l ,2.3,4-tetr ahydro-5H- [l]benzopyrano[3,4-c]pyridineis reacted with 3-(3,4-dimethoxyphenyl)propyl bromide in absoluteethanol. in the presence of anhydrous sodium carbonate to' give5,5-dimethyl-l0-hydroxy-8-(3-methyl-2- octyl)-3-[-3,4dimethoxyphenyl)propyl}l ,2,3,4- tetrahydro-5H[ l ]benzopyrano[3,4-c]pyridine.

EXAMPLE l5 5,5-Dimethyl-lO-hydroxy-8-(3-methyl-2-octyl)-3-[1- (2,4,6 I-tribromophenyl)-ethyl]-l ,2,3 ,4-tetr'ahydro-5H[ l]benzopyranoB,4-c]pyridine Following a procedure similar to thatdescribed in Example Shereinabove, 5,5-dimethyll 0-hydroxy-8-(3-methyl-2-octyl)-1,2,3,4-tetrahydro-5H- [l]benzopyrano[3,4-c]pyridine isreacted with l-(2,3,6-tribromophenyl)ethyl bromide in the presence ofanhydrous sodium carbonate to give 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-3-[ 1-(2,4,6- tribromophenyl )-ethyl]-l,2,3,4-tetrahydro-- 5H[ l ]benzopyrano[ 3,4-c]pyridine.

EXAMPLE 16 5 ,5Dimethyll O-hydroxy8-( 3-methyl-2-octyl )-3-[ 4-(4-nitrophenyl)butyl]-l ,2,3,4-tetrahydro-5H-[ 1 ]benzopyrano-13 ,4-c]pyridine Following a procedure similar to that described in Example 3hereinabove, 5,5-dimethyl-l0 hydroxy-8- (3-methyl-2-octyl l ,2,3,4-tetrahydro-5H- [1]benzopyrano[3,4 c]pyridine is reacted with 4-(4-nitrophenyl)butylbromide in the presence of anhydrous sodium carbonateto give 5,5-dimethyl-l0- EXAMPLE 34 I I l-Hydroxy-3-( 2-propynyl )'-5 ,5,8-trimethyl-H- ll]benzopyrano[3,4-cl-piperidine Following a proceduresimilar to that described Example 3 hereinabove,lO-hydroxy-S,5,8-trimethyl- 5H-[l]benzopyrano[3,4-c1pyridine is reactedwith 3- bromo-l-propyne in absolute ethanol in the presence of anhydroussodium carbonate to give l0-hydroxy 3- (Z-propynyl)5,5,8-trimethyl-5H-[l ]-benzopyrano[3,4- c]piperidine.

EXAMPLE 35 5 ,S-Dimethyll 0-hydroxy-8-( 3-methyl-2 -octyl )-3-( 2-propynyl)-5H-[ l ]benzopyranol3,4-c]piperidine Following a proceduresimilar to that described in Example 3 hereinabove,5,5-dimethyl-l0-hydroxy-8- (3-methyl-2octyl)-5H[ l ]benzopyrano[3,4-c]piperidine is reacted with 3-bromo-l-propyne in absolute ethanol inthe presence of anhydrous sodium carbonate to give5,5-dimethyl-l0-hydroxy-8-(3- methyl-2-octyl)-3-(2-propynyl)-5H-[ 1]ben- I zopyrano[3,4-c]-piperidine.

EXAMPLE 36 3-Cinnamyl-5,5-dimethyl-l0-hydroxy-8-(3methyl-2- octyl )-5H'[1 ]benzopyrano[ 3,4-c]piperidine Following a procedure similar to thatdescribed in Example 3 hereinabove, 5,5-dimethyl-1O-hydroXy-S(3methyl-2-octyl)-5H-[1]benzopyrano[3.4-

c]piperidine is reacted'with cinnamyl chloride in absolute ethanol inthe presence of anhydrous sodium carbonate to give3-cinnamyl-5,S-dimethyl-lO-hydroxy-8- (3-methyl-2-octyl )-5H-[ 1]benzopyrano[3,4-c]- piperdine.

EXAMPLE 37 5,5-Dimethyl-lO-hydroxy-8-(3-methyl-2-octyl)-3-[4-(4-nitrophenyl)butyl ]-5H-[ 1 ]benzopyrano[3.4- c]piperidine Following aprocedure similar to that described in Example 3 hereinabove,5,5-dimethyl-lO-hydroxy-8- (3-methyl-2octyl )-5H-[ 1 ]benzopyrano[3,4-c]piperidine is reacted with 4-(4-nitrophenyl)butyl bromide in absoluteethanol in the presence of anhy- Following a procedure similar to thatdescribed in Example 3 hereinabove, 5,Sdimethyl-10-hydroxy-8-(3-methyl-2-octyl )-5H-[ 1 ]benzopyrano[3,4-c]piperidine is reacted with3-[l-(3,4-methylenedioxyphenyl)-1- butenyl]bromide in absolute ethanolin the presence of anhydrous sodium carbonate to give 5,5-dimethyl-l0-hydroxy-8-(3-methyl-2-octyl)-3- 3[ l-(3,4-methylenedioxyphenyl)-l-butenyl] -5H-[ 1 ]benzopyrano[3,4-c]-piperidine.

EXAMPLE 39 5.5-Dimethyl-l0-hydroxy-8(3methyl-2-octyl)-3- 3-[l-(4-acetylaminophenyl)-l-butenyl] 5H-[ 1 ]ben- 5zopyranol3.4-c]-piperidine l Following a procedure similar to thatdescribed in Example 3 herei nabove. 5.5dimetliyl-l0-hydroxy-8-(3-met'hyl-2-oct'yl )-5H-[ l ]benzopyrariol 3,4- ,c]piperidine isreacted 'wit-h' 3-[1-(4- acetylaminopheny)-l-butenyllbromide in absoluteethanol in the presence ofanhydrous sodiumcarbonate to give5,5-dimethyl-lO-hydroxy8-(3-methyl-2-octyl)-3- zopyrano[ 3 ,4-cl-piperidine.

EXAMPLE 40 zopyrano-[3,4-c]piperidine Following a procedure similar tothat described in Example 3 hereinabove, 5,5-dimethyl-l0-hydroxy-8(3-methyl-2=octyl)-5H-['1 ]benzopyrano[3,4- c]piperidine is reacted with4-[1-(3- give 5,5-dimethyl-lO-hydroxy-8('3-methyl-2-octyl)-3-4-[1-(3-trifluoromethylphenyl)-l-butenyl] -5H- [1]benzopyrano-[3.4-c]piperidine.

EXAMPLE 41 5 .SDimethyll 0-hydroxy-8-( 3-methyl-2-octyl )-3-( 3-phenyl-Z-propynyl )-5H-[ 1 ]benzopyrano[3,4- c]piperidine Following aprocedure similar-to that described in Example 3 hereinabove,5,5-dimethyl-IO-hydroxy-S- (3-meth-yl-2--octyl )-5H-[ 1]benzopyrano[ 3,4- c]piperidine-is reacted with 3-phenyl-2-propynyl bromide in absoluteethanol in the presenceof anhydrous sodium carbonate to give5,5-dimethyl-l0-hydroxy-8-(3-methyl-2-octyl)-3-(3-phenyl-2-propynyl)-5H-[1]-benzopyrano[3,4-c]piperidine.

EXAMPLE 42 3-Benzyl-8-hydroxy-10-methyl-5-oxo-l ,2,3,4- tetrahydro-5H-[l ]-benzopyrano[3,4-c]pyridine is obtained by reaction ofl-benzyl-3-carbethoXy-4- piperidone with 5-methylresorcinol according tothe procedure described above in Example S-A.

EXAMPLE 43 8-l-lydroxyl O-n'tethyl-S-oxo- 1 ,2,3,4-tetrahydro-5 H-[l]benzopyrano-[3,4-c]pyridine is prepared by catalytic debenzylation of3-benzyl-8-hydroxyl O-methyl-5-oxo-l ,2,3,4 tetrahydro-5H[ l]-benzopyrano[ 3,4-c]pyridine accordingto theprocedure described abovein Example S-B.

EXAMPLE 44 8-Hydroxy-5 ,5 ,1 O -trimethyll,2,3,4-.tetrahydro-5H- [l]benzopyrano[3,4-c1pyridine is prepared by reacting8-hydroxy-lO-methyl-S-oxol,2,3,4-tetrahydro-5H-[ l ]benzopyrano[3,4-c]-pyridine with methyl magnesium iodide according to the proceduredescribed above in Example 6.

trifluoromethylphenyl)-1-butenyl]bromide in absolute ethanol in thepresence'of'anhydrous sodium carbonate EXAMPLE 4 S I a8-Hydroxy-3,5,5,IO-tetramethyl-l.,2,3,4-tetrahydro- 5H-[ 1 ]benzopyrano[3,4-c1pyridine is prepared by reaction of 8-hydroxy'lO-methyl 5,5dimethyl-l,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4- c]-pyridine withmethyl bromide in the presence of anhydrous sodium carbonate accordingto the procedure described above in Example 3.

EXAMPLE 4.6

3-Benzyl-8-hydroxy-5,5,lO-trimethyl-l,2,3,4- tetrahydro-5H-[ I]-benzopyrano[3,4-c]pyridine is prepared by reacting3-berizyl-8hydroxy-lOmethyl- 5-oxo-l ,2,3,4-tetrahydro-5H-[ l}benzopyrano-[ 3.4- c]pyridine with methyl magnesium bromide in anisoleaccording to the procedure described above in Example 6.

EXAMPLE 47 S-Hydroxy-l O-methyl-5,5-dihexyl-l ,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridine is prepared by reacting8-hydroxy-lO-methyl-Soxol,2,3,4-tetrahydro-5l-l-[ l]benzopyrano[3,4-c1pyridine with n-hexyl magnesium bromide according tothe procedure described above in Example 6.

EXAMPLE 48 3-Cinnamyl-8-hydroxy-5,5,IO-trimethyI-I 2,3,4-tetrahydro-5l-l-[ l ]-benzopyrano[ 3,4-c]pyridine is prepared byreacting 8-hydroxy-5,5,lO-trimethyl- 1,2,3,4-tetrahydro-5l-l-[ l]benzopyrano[ 3,4-c]- pyridine with cinnamyl chloride in the presence ofanhydrous sodium carbonate according to the procedure described above inExample 3.

EXAMPLE 49 3-Acetyl-8-hydroxy-5 ,5, l O-trimethyl-l ,2,3,4-tetrahydro-5H-[1]-benzopyrano[3.4-c]pyridine as prepared by reacting8-hydroxy-5,5,lO-trimethyll,2,3,4-tetrahydro-5H-[ l ]benzopyrano[3,4-c]- pyridine with an equimolar amount of acetyl chloride in abenzene solution and in the presence of triethylamine according to theprocedure described above in Example l0.

EXAMPLE 5O 3-Pheny1acetyl-S-hydroxy-S,5,10'trimethyl-l,2,3,4-tetrahydro-5H-[ l ]benzopyrano[ 3,4-c]pyridine is prepared by reacting8-hydroxy-5,5,10-trimethyll,2,3,4-tetrahydro-5H-[ l ]benzopyrano[3,4-c]-pyridine with phenylacetyl chloride in a benzene solution and in thepresence of pyridine according to the procedure described above inExample 1 1.

EXAMPLE 51 3-(2-Phenylethyl)-8-hydroxy-5,5,IO-trimethyl-l,2,3,4-tetrahydro-5H-[ l ]benzopyrano[3,4-c]pyridine is prepared by reacting3-phenylacetyl-8-hydroxy- 5,5,1 O-trimethyl-l ,2,3,4-tetrahydro-5l-l-[l]benzopyrano[3,4-c]pyridine with lithium aluminum hydride in atetrahydrofuran solution according to the procedure described above inExample 12.

EXAMPLE 52 EXAMPLE 53 3-[ 3-( 3 ,4-Dimethoxyphenyl )propyl]-8-hydroxy- 5,5 l O-trimethyl-l ,2.3,4-tetrahydro5H- [1]benzopyrano[ 3,4-c]pyridineis prepared by reacting 8-hydroxy-5,5,lO-trimethyll,2,3,4-tetrahydro5H-[l ]benzopyrano[ 3.4-clpyridine with 3-(3,4-dimethoxyphenyl)propylbromide in absolute ethanol in the presence of anhydrous sodiumcarbonate according to the procedure described above in Example 3.

EXAMPLE 54 3-[ l-(2,4,6-Tribromophenyl)ethyl]-8-hydroxy-5,5.10-trimethyl-l ,2,3,4-tetrahydro-5 H-[ l ]benzopyrano[ 3,4- clpyridine isprepared by reacting 8-hydroxy-5,5,10-trimethyl 1,2,3,4-tetrahydro'5H-[l ]benzopyrano[3,4-c]pyridine with l-(2,4,6-tribromophenyl)-ethylbromide in absolute ethanol in the presence of anhydrous sodiumcarbonate according to the procedure described above in Example 3.

EXAMPLE 55 3-[4-( 4-Nitrophenyl )butyl]-8-hydroxy-5 .5 .10- trimethyl-l,2,3,4-tetrahydro-5H-[ l ]benzopyrano[ 3 ,4-

c]pyridine is prepared by reacting8-hydroxy-5,5,lO-trimethyll,2,3,4-tetrahydro-5H-[1]benzopyrano[3.4-c]pyridinewith 4-(4-nitrophenyl)butyl bromide in absolute ethanol in the presenceof anhydrous sodium carbonate according to the procedure described abovein Example 3.

EXAMPLE 56 3-[ 2-(4-Methylmercaptophenyl )ethyll-8-hydroxy- 5,5,1O-trimethyl-l ,2,3,4-tetrahydro-5H- [1]benzopyrano[3,4-c]pyridine isprepared by reacting 8-hydroxy-5,5,10-trimethyll,2,3,4-tetrahydro-5H-[ l]benzopyrano[3,4-c]pyridine with 2-(4-methylmercaptophenyl )-ethylbromide in absolute ethanol in the presence of anhydrous sodiumcarbonate according to the procedure described above in Example 3.

EXAMPLE 57 3- 3-[3,4-Methylenedioxyphenyl)-l-butenyl] -8- hydroxy-5 ,5,l O-trimethyl-l ,2,3 ,4-tetrahydro-5H- [1]benzopyrano[3,4-c]pyridine isprepared by reacting 8-hydroxy-5,5,l0-trimethyll,2,3;4-tetrahydro5H-[1]benzopyrano[3,4-c]pyridine with3-[1-(3,4-methylenedioxyphenyl)-l-butenyl] bromide in absolute ethanolin the presence of anhydrous carbonate according to the proceduredescribed above in Example 3.

EXAMPLE 58 3- 3-[1-(4-Acetylaminophenyl)-l-butenyl] -8- hydroxy-5,5,lO-trimethyl-l ,2,3,4-tetrahydro-H- [l]benzopyrano[ 3,4-c1pyridine isprepared by reacting 8-hydroxy-5,5,lO-trimethyll,2,3,4-tetrahydro-5H-[ l]benzopyrano[3,4-c ]pyridine with 3-[l-(4-acetylaminophenyl)-l-butenyl]bromide in absolute ethanol in the presence of anhydrous sodiumcarbonate according to the procedure described above in Example 3.

EXAMPLE 59 3- 4-[l-(3-Trifluoromethylphenyl)-l-butenyl] -8-hydroxy-5,5,lO-trimethyll ,2,3,4-tetrahydro-5H-[l]benzopyrano[3,4-c]pyridine is prepared by reacting8-hydroxy-5,5,lO-trimethyll,2,3,4-tetrahydro-5H-[ l]benzopyrano[3,4-c]pyridine with4-[l-(3-trifluoromethylphenyl)-1-butenyl] bromide in absolute ethanol inthe presence of anhydrous sodium carbonate according to the proceduredescribed above in Example 3.

EXAMPLE 6O 3 -Cyclopropylcarbonyl-8-hydroxy-5 ,5 lO-trimethyll,2,3,4-tetrahydro-5H-[ l ]benzopyrano[ 3,4-c]pyridine isprepared by reacting 8-hydroxy-5,5,IO-trimethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c1pyridine withcyclopropylcarbonyl chloride in a benzene solution and in the presenceof pyridine according to the procedure described above in Example 21.

EXAMPLE 6]3-Cyclopropylmethyl-8-hydroxy-5,5,lO-trimethyll,2,3,4-tetrahydro-5H-[ l]benzopyrano[3,4-c]pyridine is prepared by reducing3-cyclopropylcarbonyl-8- hydroxy-5,5, l O-trimethyll,2,3,4tetrahydro-5H- [l]benzopyrano[3,4pyridine with lithium aluminumhydride according to the procedure described above in Example 22.

EXAMPLE 623-(3-Phenyl-2-propynyl)-8-hydroxy-5,5,IO-trimethyll,2,3,4-tetrahydro-5H-[l ]benzopyrano[3,4-c]pyridine is prepared by reacting8-hydroxy-5,5,IO-trimethyll,2,3,4-tetrahydro-5H-[ l ]-benzopyrano[3,4-clpyridine with 3-phenyl-2propynyl bromide in absolute ethanol in thepresence of anhydrous sodium carbonate according to the proceduredescribed above in Example 3.

EXAMPLE 63 3-Allyl-8-hydroxy-5 ,5, l O-trimethyll ,2,3 ,4-tetrahydro-5H-[ 1 }-benzopyrano[3,4-c]pyridine is prepared by reacting8-hydroxy-5,5,lO-trimethyll,2,3,4-tetrahydro-5H-[ l ]benzopyrano[3,4-c]-pyridine with 3-bromo-l-propene in absolute ethanol 1n the presence ofanhydrous sodium carbonate accordng to the procedure described above inExample 3.

EXAMPLE 64 3-(2 Propynyl)-8-hydroxy-5,5,IO-trimethyl-1,23,4-tetrahydro-5H-[ l ]benzopyrano[3,4-c]pyridine is prepared by a reacting8-hydr0xy-5,5,lO-trimethyll,2,3,4-tetrahydro-5H-[ l ]benzopyrano-[3.4-

clpyridine with 3-bromo-l-propyne in absolute ethanol in the presence ofanhydrous sodium carbonate according to the procedure described above inExample 2-D.

EXAMPLE 65 3-( trans-3-Chloroallyl )-8-hydroxy-5 ,5 lO-trimethyll,2,3,4-tetrahydro-5H-[ l ]benzopyrano[3,4-c1pyridine isprepared by reacting8-hydroxy-5,5,IO-trimethyll,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridinewith trans-l,3-dichloro-l-propene in absolute ethanol in the presence ofanhydrous sodium carbonate according to the procedure described above inExample 4.

EXAMPLE 66 8-Acetoxy-3 ,5 ,5, l O-tetramethyll ,2,3 ,4-tetrahydro- 5H-[1 ]benzopyrano[ 3,4-c]pyridine is prepared by reacting8-hydroxy-3,5,5,l0- tetramethyl-l ,2,3,4-tetrahydro-5H-[l]benzopyrano[3,41-pyridine with acetic anhydride according th theprocedure described above in Example 24.

EXAMPLE 67 8-Methoxy-3 ,5 ,5 lO-tetramethyl-l ,2,3 ,4-tetrahydro- 5H-[ 1]benzopyrano[3,4-c]pyridine is prepared by reacting 8-hydroxy-3,5,5,l0-tetramethyl-l ,2,3 ,4-tetrahydro-5H- [l]benzopyrano[3,4-cjpyridine withmethyl iodide in the presence of sodium ethoxide according to theprocedure described above in Example 25.

EXAMPLE 68 8-Carbamyloxy-3,5 ,5 l O-tetramethyl-l ,2,3 ,4-tetrahydro-5H-[ 1 ]-benzopyrano[3,4-c]pyridine is prepared by reacting8hydroxy-3,5,5,lO-tetramethyll,2,3,4-tetrahydro-5H-[ l]benzopyrano[3,4-c]- pyridine with an equimolar amount of phosgene inthe presence of dimethylaniline, and reacting the resultingchloroformate with liquid ammonia according to the procedure describedabove in Example 26.

EXAMPLE 69 EXAMPLE 7O 8( N ,N-Dimethylcarbamyloxy )-3 ,5,5 lO-tetramethyll,2,3,4-tetrahydro-5H-[ l ]benzopyrano[3,4-c]pyridine isprepared by reacting 8-hydroxy-3,5,5,l0- tetramethyl-l,2,3,4tetrahydro-5H- [l]benzopyran0[3,4-c]pyridine with an equimolaramount of phosgene in the presence of dimethylaniline,

1. A COMPOUND HAVING THE FORMULA: